Catalytic Asymmetric Synthesis of Unsaturated Compounds

The catalytic asymmetric synthesis of unsaturated compounds encompasses a suite of methodologies designed to construct alkenes, dienes, allenes and related motifs with high stereochemical precision. Such approaches harness chiral catalysts—often transition‐metal complexes bearing bespoke ligands—to orchestrate the selective addition of nucleophiles or electrophiles across carbon–carbon multiple bonds. Key strategies include asymmetric hydrofunctionalization, cycloaddition and cross‐coupling cascades, each tuned to deliver defined stereogenic centres and controlled olefin geometry. Recent advances have focused on expanding the scope of carbon‐based nucleophiles, improving catalyst turnover and achieving stereodivergent syntheses of E/Z isomers. The global importance of these methods lies in their atom economy, mild reaction conditions and capacity to furnish chiral building blocks for pharmaceuticals, agrochemicals and advanced materials.

Research from Nature Portfolio

Recent studies have demonstrated an unprecedented asymmetric formal sp2-hydrocarbonation of 1,3-dienes and alkynes via a palladium-hydride catalyst. This protocol achieves hydroalkenylation, hydroallenylation and hydroketenimination by cleaving inert sp2 C–H bonds of carbon nucleophiles and engaging a cascade that integrates hydroalkylation with a Wittig‐type olefination. The result is a range of di- to tetra-substituted alkenes and allenes formed with excellent regio-, diastereo- and enantioselectivity, including stereodivergent access to all four isomers of a 1,4-diene scaffold.

An enantioselective Pd/WingPhos-catalysed cycloaddition approach has enabled direct assembly of spirocyclic frameworks from 1,3-enynes and cyclic C–H bonds. The chiral catalyst suppresses by-product formation and directs four-carbon dielectrophiles into spirocycles bearing diverse heterocyclic or carbocyclic rings. Broad functional-group tolerance and high enantioselectivity underscore its utility in synthesising motifs of pharmaceutical relevance.

A foundational rhodium-catalysed allylation method achieves regio- and enantioselective N-allylic indole synthesis by coupling aryl hydrazines with allenes. The exclusive N-selectivity and excellent enantioselectivity of this protocol have established a benchmark for asymmetric allylation of heteroatom nucleophiles, enabling scalable access to chiral indole derivatives.

Catalytic Asymmetric Synthesis of Unsaturated Compounds publication trend

The graph below shows the total number of articles in catalytic asymmetric synthesis of unsaturated compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Enantioselectivity: Preference for formation of one enantiomer over its mirror image in a chiral product.

Regioselectivity: Tendency for a chemical reaction to occur at one position over alternative sites on an unsymmetrical substrate.

Stereogenic centre: Atom at which exchange of two ligands creates stereoisomers that are non-superimposable mirror images.

Hydrofunctionalization: Addition of a hydrogen and a functional group across a carbon–carbon multiple bond in a single process.

Atom economy: Measure of efficiency defined as the proportion of reactant atoms incorporated into the desired product.

References

1. Asymmetric formal sp2-hydrocarbonations of dienes and alkynes via palladium hydride catalysis. Nature Communications (2023).
2. Direct access to spirocycles by Pd/WingPhos-catalyzed enantioselective cycloaddition of 1,3-enynes. Nature Communications (2021).
3. Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines. Nature Communications (2015).
4. Enantioselective Hydroalkoxylation of 1,3-Dienes via Ni-Catalysis. Journal of the American Chemical Society (2023).
5. Understanding the Regiodivergence between Hydroarylation and Trifluoromethylarylation of 1,3-Dienes Using Anilines in HFIP. JACS Au (2024).
6. Nickel-catalyzed regio- and enantio-selective Markovnikov hydromonofluoroalkylation of 1,3-dienes. Chemical Science (2022).